Biology subjects

Suzuki, H.

Publications and source records attributed to Suzuki, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Heart generation via blastocyst complementation in Mesp1/2-deficient mice

Heart transplantation is the only curative option available for patients with advanced heart failure. However, donor organ shortage and graft rejection remain critical challenges in heart transplantation. Blastocyst complementation using pluripotent stem cells (PSCs) can be used to generate organs such as the pancreas and kidneys in animal models with abnormalities in essential developmental genes. Nonetheless, whether functional adult hearts can be generated with blastocyst complementation remains unclear, and it is unknown if parenchyma, blood vessels, and stroma can be generated concomitantly from PSCs using blastocyst complementation to avoid graft rejection. Here, we show the generation of functional adult hearts in acardiac Mesp1 and Mesp2 double-knockout (Mesp1/2-DKO) mice via blastocyst complementation using mouse PSCs. Our result shows that the generated hearts were structurally and functionally normal and restored embryonic lethality in Mesp1/2-DKO mice. All four cardiovascular lineages, including cardiomyocytes, vascular endothelial cells, smooth muscle cells, and cardiac fibroblasts, were virtually entirely derived from exogenous PSCs in the myocardium. Exogenous rat PSCs also generated rat-derived xenogeneic hearts in Mesp1/2-DKO mice via interspecies blastocyst complementation. Thus, blastocyst complementation is a viable technique for generating hearts derived from PSCs and may represent significant progress toward generating rejection-free hearts.

cell biology↗

bioRxiv2023

Glioblastoma initiation, migration, and cell types are regulated by core bHLH transcription factors ASCL1 and OLIG2

Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex driver mutations and glioma stem cells (GSCs). The neurodevelopmental transcription factors ASCL1 and OLIG2 are co-expressed in GBMs, but their role in regulating the heterogeneity and hierarchy of GBM tumor cells is unclear. Here, we show that oncogenic driver mutations lead to dysregulation of ASCL1 and OLIG2, which function redundantly to initiate brain tumor formation in a mouse model of GBM. Subsequently, the dynamic levels and reciprocal binding of ASCL1 and OLIG2 to each other and to downstream target genes then determine the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in defining GSCs by upregulating a collection of ribosomal protein, mitochondrial, neural stem cell (NSC), and cancer metastasis genes - all essential for sustaining the high proliferation, migration, and therapeutic resistance of GSCs.

neuroscience↗

bioRxiv2023

Regional random mutagenesis driven by multiple sgRNAs and diverse on-target genome editing events to identify functionally important elements in non-coding regions

Functional regions that regulate biological phenomena are interspersed throughout eukaryotic genomes. The most definitive approach for identifying such regions is to confirm the phenotype of cells or organisms in which specific regions have been mutated or removed from the genome. This approach is invaluable for the functional analysis of genes with a defined functional element, the protein-coding sequence. In contrast, no functional analysis platforms have been established for the study of cis-elements or microRNA cluster regions consisting of multiple microRNAs with functional overlap. Whole-genome mutagenesis approaches, such as via N-ethyl-N-nitrosourea (ENU) and gene trapping, have greatly contributed to elucidating the function of coding genes. These methods almost never induce deletions of genomic regions or multiple mutations within a narrow region. In other words, cis-elements and microRNA clusters cannot be effectively targeted in such a manner. Herein, we established a novel region-specific random mutagenesis method named CRISPR-& Transposase-based RegionaL Mutagenesis (CTRL-Mutagenesis). We demonstrated that CTRL-mutagenesis randomly induces diverse mutations within target regions in murine embryonic stem cells. Comparative analysis of mutants harbouring subtly different mutations within the same region would facilitate the further study of cis-element and microRNA clusters. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/557308v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@f70563org.highwire.dtl.DTLVardef@182dc6borg.highwire.dtl.DTLVardef@550e32org.highwire.dtl.DTLVardef@16f7dd_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2023

Inference of Selective Force on House Mice Genomes during Secondary Contact in East Asia

The house mouse (Mus musculus), commensal to humans, has spread globally via human activities, leading to secondary contact between genetically divergent subspecies. This pattern of genetic admixture can provide insights into the selective forces at play in this well-studied model organism. Our analysis of 163 house mouse genomes, with a particular focus on East Asia, revealed substantial admixture between the subspecies castaneus and musculus, particularly in Japan and southern China. We revealed, despite the admixture, all Y chromosomes in the East Asian samples belonged to the musculus-type haplogroup, potentially explained by genomic conflict under sex ratio distortion due to varying copy numbers of ampliconic genes on sex chromosomes. We also investigated the influence of selection on the post-hybridization of the subspecies castaneus and musculus in Japan. Even though the genetic background of most Japanese samples closely resembles the subspecies musculus, certain genomic regions overrepresented the castaneus-like genetic components, particularly in immune-related genes. Furthermore, a large genomic block containing a vomeronasal/olfactory receptor gene cluster predominantly harbored castaneus-type haplotypes in the Japanese samples, highlighting the crucial role of olfaction-based recognition in shaping hybrid genomes.

evolutionary biology↗

bioRxiv2023

Wnt5a-Ror2 signaling activates p62-Nrf2 axis in reactive astrocytes after brain injury

In the brains under pathological conditions, astrocytes become reactive astrocytes that exhibit various context-dependent functions through the regulation of specific signaling pathways and transcriptional mechanisms in response to environmental changes. Reactive astrocytes induced in injured brains begin proliferating and play a role in promoting protection and repair of damaged tissues, but the relationship between the proliferative characteristics and tissue-protective and repair functions of reactive astrocytes remains unclear. Here, we show that growth factor signaling elicited by bFGF and HB-EGF, whose expression is up-regulated in the injured brains, acts synergistically with inflammatory cytokine signaling in astrocytes, thereby markedly up-regulating gene expression of the Ror-family protein Ror2, a receptor for Wnt5a. Activation of Wnt5a-Ror2 signaling in astrocytes results in intracellular accumulation of phosphorylated p62, thereby activating antioxidative transcription factor Nrf2. Finally, we provide evidence demonstrating that forced activation of Wnt5a-Ror2-p62-Nrf2 signaling axis in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.

molecular biology↗

bioRxiv2023

Gas6 ameliorates intestinal mucosal immunosenescence to prevent the translocation of a gut pathobiont, Klebsiella pneumoniae, to the liver

Immunosenescence refers to the development of weakened and/or dysfunctional immune responses associated with aging. Several commensal bacteria can be pathogenic in immunosuppressed individuals. Although Klebsiella pneumoniae is a commensal bacterium that colonizes human mucosal surfaces, the gastrointestinal tract, and the oropharynx, it can cause serious infectious diseases, such as pneumonia, urinary tract infections, and liver abscesses, primarily in elderly patients. However, the reason why K. pneumoniae targets elderly population remains unclear. This study aimed to determine how the intestinal immune response of the host to K. pneumoniae varies with age. To this end, the study analyzed an in vivo K. pneumoniae infection model using aged mice, as well as an in vitro K. pneumoniae infection model using a Transwell insert co-culture system comprised of epithelial cells and macrophages. In this study, we demonstrate that growth arrest-specific 6 (Gas6), released by intestinal macrophages that recognize K. pneumoniae, inhibits bacterial translocation from the gastrointestinal tract by enhancing tight-junction barriers in the intestinal epithelium. However, in aging mice, Gas6 was hardly secreted under K. pneumoniae infection due to decreasing intestinal mucosal macrophages; therefore, K. pneumoniae can easily invade the intestinal epithelium and subsequently translocate to the liver. Moreover, the administration of Gas6 recombinant protein to elderly mice prevented the translocation of orally infected K. pneumoniae from the gastrointestinal tract and significantly prolonged their survival. From these findings, we conclude that the age-related decrease in Gas6 secretion in the intestinal mucosa is the reason why K. pneumoniae can be pathogenic in the elderly, thereby indicating that Gas6 could be effective in protecting the elderly against infectious diseases caused by gut pathogens. Author SummaryAging causes a weakened/dysfunctional human immune system, reducing the ability to combat pathogens. Understanding the molecular mechanisms underlying age-related immunosenescence is critical for the development of preventive therapies against bacterial infectious diseases in elderly individuals. Klebsiella pneumoniae is a representative "pathobiont" that causes serious systemic infections such as pneumonia, urinary tract infections, and liver abscesses, mainly in the elderly. However, it remains unclear how K. pneumoniae targets the elderly population. Here, we show that growth arrest-specific 6 (Gas6), released by intestinal macrophages that recognize K. pneumoniae, inhibits bacterial invasion into the intestinal epithelium and subsequent translocation to the liver. However, in elderly mice, Gas6 is hardly secreted due to decreased intestinal mucosal macrophages; therefore, K. pneumoniae can easily translocate to the liver from the gastrointestinal tract. We concluded that the reason K. pneumoniae can be pathogenic to the elderly is the age-related decrease in Gas6 secretion in the intestinal mucosa. Moreover, we revealed that the administration of Gas6 to elderly mice significantly prevented systemic translocation of orally infected K. pneumoniae. Our findings provide new insights into the prevention of infectious diseases in the elderly.

microbiology↗

bioRxiv2022

Identification of basic helix-loop-helix transcription factors that activate betulinic acid biosynthesis by RNA-sequencing of hydroponically cultured Lotus japonicus

Although triterpenes are ubiquitous in plant kingdom, their biosynthetic regulatory mechanisms are limitedly understood. Here, we found that hydroponic culture dramatically activated betulinic acid (BA) biosynthesis in the model Fabaceae Lotus japonicus, and investigated its transcriptional regulation. Fabaceae plants develop secondary aerenchyma (SA) on the surface of hypocotyls and roots during flooding for root air diffusion. Hydroponic culture induced SA in L. japonicus and simultaneously increased the accumulation of BA and the transcript levels of its biosynthetic genes. RNA-sequencing of soil-grown and hydroponically cultured plant tissues, including SA collected by laser microdissection, revealed that several transcription factor genes were co-upregulated with BA biosynthetic genes. Overexpression of LjbHLH32 and LjbHLH50 in L. japonicus transgenic hairy roots upregulated the expression of BA biosynthesis genes, resulting in enhanced BA accumulation. However, transient luciferase reporter assays in Arabidopsis mesophyll cell protoplasts showed that LjbHLH32 transactivated promoters of biosynthetic genes in the soyasaponin pathway but not the BA pathway, like its homolog GubHLH3, a soyasaponin biosynthesis regulator in Glycyrrhiza uralensis. This suggested the evolutionary origin and complex regulatory mechanisms of BA biosynthesis in Fabaceae. This study sheds light on the unrevealed biosynthetic regulatory mechanisms of triterpenes in Fabaceae plants. HighlightHydroponic culture enhanced betulinic acid synthesis in Lotus japonicus. RNA-sequencing and functional characterization experiments suggest that LjbHLH32 and LjbHLH50 are the transcription factors activating betulinic acid biosynthesis.

plant biology↗

bioRxiv2022

Prophages and plasmids display opposite trends in the types of accessory genes they carry

2Mobile genetic elements (MGEs), such as phages and plasmids, often possess accessory genes encoding bacterial functions, facilitating bacterial evolution. Are there evolutionary rules governing the arsenal of accessory genes MGEs carry? If such rules exist, they might be reflected in the types of accessory genes different MGEs carry. To test this hypothesis, we compare prophages and plasmids with respect to the frequencies at which they carry antibiotic resistance genes (ARGs) and virulence factor genes (VFGs) in the genomes of 21 pathogenic bacterial species using public databases. Our results indicate that prophages tend to carry VFGs more frequently than ARGs in three species, whereas plasmids tend to carry ARGs more frequently than VFGs in nine species. In Escherichia coli, where these trends are detected, prophage-borne VFGs encode a much narrower range of functions than do plasmid-borne VFGs, typically involved in damaging host cells or modulating host immunity. In the species where the above trends were not detected, ARGs and VFGs are barely found in prophages and plasmids. These results indicate that MGEs differentiate in the types of accessory genes they carry depending on their infection strategies, suggesting an evolutionary rule governing horizontal gene transfer mediated by MGEs.

microbiology↗

bioRxiv2022

Childhood cancer mutagenesis caused by a domesticated DNA transposase

Genomic rearrangements are a hallmark of most solid tumors, including medulloblastoma, one of the most common brain tumors in children. Childhood cancers involve dysregulated cell development, but their mutational causes remain largely unknown. One of the most common forms of medulloblastoma is caused by ectopic activation of Sonic Hedgehog (SHH) signaling in cerebellar granule cell progenitors, associated with genetic deletions, amplifications, and other oncogenic chromosomal rearrangements. Here, we show that PiggyBac Transposable Element Derived 5 (Pgbd5) promotes tumor development in multiple developmentally-accurate mouse models of SHH medulloblastoma. Most mice with Pgbd5 deficiency do not develop tumors, while Pgbd5-deficient mice maintain largely normal cerebellar development. Mouse medulloblastomas expressing Pgbd5 exhibit significantly increased numbers of somatic structural DNA rearrangements, with PGBD5-specific transposon sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. Therefore, this study identifies PGBD5 as a primary medulloblastoma mutator and provides a genetic mechanism responsible for the generation of somatic oncogenic DNA rearrangements in childhood cancer. One-Sentence SummaryInduction of somatic oncogenic mutations by the DNA transposase PGBD5 in cerebellar progenitor cells promotes medulloblastoma development.

cancer biology↗

bioRxiv2022

Nuclear auxin signaling is essential for organogenesis but not for cell survival in the liverwort Marchantia polymorpha

Auxin plays pleiotropic roles in plant development via gene regulation upon perception by the receptors TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX (TIR1/AFBs). This nuclear auxin signaling (NAS) originated in the common ancestor of land plants. Although complete loss of TIR1/AFBs causes embryonic lethality in Arabidopsis thaliana, it is unclear whether the requirement for TIR1-mediated auxin perception in cell viability can be generalized. The model liverwort Marchanita polymorpha has a minimal NAS system with only a single TIR1/AFB, MpTIR1. Here we show by genetic, biochemical, and transcriptomic analyses that MpTIR1 functions as an evolutionarily conserved auxin receptor. Null mutants and conditionally knocked-out mutants of MpTIR1 were viable but incapable of forming any organs and grew as cell masses. Principal component analysis performed using transcriptomes at various developmental stages indicated that MpTIR1 is involved in the developmental transition from spores to organized thalli, during which apical notches containing stem cells are established. In Mptir1 cells, stem-cell- and differentiation-related genes were up- and down-regulated, respectively. Our findings suggest that, in M. polymorpha, NAS is dispensable for cell division but essential for three-dimensional body plans by establishing pluripotent stem cells for organogenesis, a derived trait of land plants.

plant biology↗

bioRxiv2022

Non-classical glycosylation determines intracellular trafficking of APP and Aβ production

A primary pathology of Alzheimers disease (AD) is A{beta} deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy (CAA). Parenchymal amyloid plaques presumably originate from neuronal A{beta} precursor protein (APP), but vascular amyloid deposits origins remain unclear. Endothelial APP expression in APP-knock-in mice was recently shown to expand CAA pathology, highlighting endothelial APPs importance. Furthermore, two types of endothelial APP--with and without O-glycans--have been biochemically identified, but only the former is cleaved for A{beta} production, indicating the critical relationship between APP O-glycosylation and processing. Here, we analyzed APP glycosylation and its intracellular trafficking in neurons and endothelial cells. Although protein glycosylation is generally believed to precede cell surface trafficking, which was true for neuronal APP, we unexpectedly observed that APP lacking O-glycans is externalized to the endothelial cell surface and transported back to the Golgi apparatus, where it then acquires O-glycans. Knockdown of genes encoding enzymes initiating APP O-glycosylation significantly reduced A{beta} production, suggesting this non-classical glycosylation pathway contributes to CAA pathology and is a novel therapeutic target.

neuroscience↗

bioRxiv2022

Mutations in OsRZF1, encoding a zinc-finger protein, causes reduced magnesium uptake in roots and translocation to shoots in rice

Magnesium (Mg) homeostasis is critical for maintaining many biological processes, but little information is available to comprehend the molecular mechanisms regulating Mg concentration in rice (Oryza sativa). To make up for the lack of information, we aimed to identify mutants defective in Mg homeostasis through a forward genetic approach. As a result of the screening of about 3,000 M2 seedlings mutated by ion-beam irradiation, we found a rice mutant that showed reduced Mg content in leaves and slightly increased Mg content in roots. Radiotracer 28Mg experiments showed that this mutant, named low magnesium content 1 (LMGC1), has decreased Mg2+ influx in the root and Mg2+ translocation from root to shoot. The MutMap method identified 7.4 kbp deletion in the LMGC1 genome leading to a loss of two genes. Genome editing using CRISPR-Cas9 further revealed that one of the two lost genes, a gene belonging to RanBP2-type zinc finger family, was the causal gene of the low-Mg phenotype. Considering this gene, named OsRZF1, has never been reported to be involved in ion transport, the phenotype of LMGC1 would be associated with a novel mechanism of Mg homeostasis in plants.

plant biology↗

bioRxiv2022

Inferring future changes in gene flow under climate change in riverscapes

Global climate change poses a significant threat to the habitat connectivity of cold-water-adapted organisms, leading to species extinctions. Because gene flow is itself a functional connectivity among wild populations, if gene flow is modeled by landscape variables, changes in population connectivity could be predicted. In this study, using a model-based riverscape genetics technique and a hydrological model to estimate water temperature, we inferred the determinants of and future changes in gene flow of the fluvial sculpin Cottus nozawae in the upstream section of the Sorachi River, Hokkaido, Japan. As a result of model selection, stream order, water temperature, slope, and distance were detected as landscape variables affecting the strength of gene flow in each stream section. In particular, the trend of greater gene flow in sections with higher stream order and lower temperature fluctuations or summer water temperatures was pronounced. The map from the model showed that gene flow is overall prevented in small tributaries in the southern area, where spring-fed environments are less prevalent. Estimating future changes in gene flow using future water temperature predictions, genetic connectivity was predicted to decrease dramatically until the end of the 21st century under IPCC representative concentration pathway scenario 8.5 (RCP8.5).

ecology↗

bioRxiv2022

ILC3s select for RORγt+ Tregs and establish tolerance to intestinal microbiota

Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory, and malignant diseases1-8. Here, we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that are specific for the microbiota and express the transcription factor ROR{gamma}t. We profiled all ROR{gamma}t+ immune cells at single cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of Tregs and lymphoid tissue-induced (LTi)-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s have interconverting potential with ROR{gamma}t+ extrathymic Aire-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific ROR{gamma}t+ Tregs and prevent their expansion as inflammatory T helper (Th)17 cells. This occurs through ILC3-mediated antigen-presentation, interleukin-2 gradients, and v integrin. Finally, single-cell analyses demonstrate that ILC3 and ROR{gamma}t+ Treg interactions are impaired in inflammatory bowel disease. Our results define a novel paradigm whereby ILC3s positively select for antigen specific ROR{gamma}t+ Tregs, and against Th17 cells, to establish immune tolerance to the microbiota and intestinal health.

immunology↗

bioRxiv2022

xcore: an R package for inference of gene expression regulators

Elucidating the Transcription Factors (TFs) that drive the gene expression changes in a given experiment is one of the most common questions asked by researchers. The existing methods rely on the predicted Transcription Factor Binding Site (TFBS) to model the changes in the motif activity. Such methods only work for TFs that have a motif and assume the TF binding profile is the same in all cell types. Given the wealth of the ChIP-seq data available for a wide range of the TFs in various cell types, we propose that the modeling can be done using ChiP-seq "signatures" directly, effectively skipping the motif finding and TFBS prediction steps. We present xcore, an R package that allows Transcription Factor activity modeling based on their ChiP-seq signatures and users gene expression data. We also provide xcoredata a companion data package that provides a collection of preprocessed ChiP-seq signatures. We demonstrate that xcore leads to biologically relevant predictions using TGF-beta induced epithelial-mesenchymal transition and rinderpest infection time-course CAGE data as examples. Availability and Implementationxcore and xcoredata R packages are freely available at www.github.com/bkaczkowski/xcore and www.github.com/mcjmigdal/xcoredata. xcore user guide is available www.bkaczkowski.github.io/xcore/articles/xcore_vignette.html. Contactb.kaczkowski@gmail.com

bioinformatics↗

bioRxiv2022

The high-throughput perturbation of long non-coding RNA reveals functional features in stem cells and across cell-types

Within the scope of FANTOM6 consortium, we perform a large-scale knockdown of 200 long non-coding RNAs (lncRNAs) in human induced pluripotent stem (iPS) cells, and systematically characterize their roles in self-renewal and pluripotency. We find 36 lncRNAs (18%) exhibiting cell growth inhibition From the knockdown of 123 lncRNAs with transcriptome profiling, 36 lncRNAs (29.3%) show molecular phenotypes. Integrating the molecular phenotypes with chromatin-interaction assays further reveals cis- and trans-interacting partners as potential primary targets. Additionally, cell type enrichment analysis identifies lncRNAs associated with pluripotency while the knockdown of LINC02595, CATG00000090305.1 and RP11-148B6.2 modulates colony formation of iPS cells. We compare our results with previously published fibroblasts phenotyping data and find that 2.9% of the lncRNAs exhibit consistent cell growth phenotype, whereas we observe 58.3% agreement in molecular phenotypes. This highlights molecular phenotyping is more comprehensive in revealing affected pathways.

genomics↗

bioRxiv2021

Tertiary lymphoid structures induced by CXCL13-producing CD4+ T cells increase tumor infiltrating CD8+ T cells and B cells in ovarian cancer

BackgroundTertiary lymphoid structures (TLSs) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. The presence of TLS is associated with a favorable prognosis in most solid malignancies. The recognition of the relevance of TLS to cancer has led to a growing interest in TLS as an immunomodulatory target to enhance tumor immunity, although how TLSs are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. MethodsTLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression were investigated in high grade serous ovarian cancer (HGSC) specimens. CXCL13 expression, which is strongly associated with TLS, and its localization in immune cells, were examined. We explored the tumor microenvironment for CXCL13 secretion by adding various inflammatory cytokines in vitro. The induction of TLS by CXCL13 was examined in a mouse model of ovarian cancer. ResultsCXCL13 gene expression correlated with TLS formation and the infiltration of T cells and B cells, and was a favorable prognostic factor for HGSC patients. The coexistence of CD8+ T cells and B-cell lineages in the TME was associated with a better prognosis of HGSC and was closely related to the presence of TLSs. CXCL13 expression was predominantly coincident with CD4+ T cells in TLSs and CD8+ T cells in TILs, and shifted from CD4+ T cells to CD21+ follicular dendritic cells as the TLS matured. Although TGF-{beta} was reported to stimulate CXCL13 production, our in vitro results revealed that CXCL13 secretion was promoted in CD4+ T cells under TGF-{beta} + IL-2-restricted conditions and in CD8+ T cells under TGF-{beta} + IL-12-rich conditions. In a mouse model of ovarian cancer, recombinant CXCL13 induced TLSs and enhanced survival by the infiltration of CD8+ T cells. ConclusionsTLS formation was promoted by CXCL13-producing CD4+ T cells and TLSs facilitated the coordinated antitumor responses of cellular and humoral immunity in ovarian cancer.

immunology↗

bioRxiv2021

Whole-genome sequencing analysis reveals the population history of Mus musculus in Madagascar

In Madagascar, the house mouse (Mus musculus) is thought to have colonized with human activities and is now one of the most abundant rodents on the island. In this study, we determined the whole-genome sequences of five Madagascar house mice captured from the wild. We examined the evolutionary history of the population by analyzing the mitochondrial and autosomal genomes. We confirmed that the mitochondrial genome lineages of Madagascar house mice formed a monophyletic clade placed at one of the most basal positions in the species. An analysis of autosomal genomic sequences indicates that the Madagascar house mice are genetically members of M. m. castaneus (CAS), but also contain genetic elements of M. m. domesticus (DOM) resulting from hybridization between subspecies. The signature of a strong population bottleneck 1000-3000 years ago was observed in both mitochondrial and autosomal genomic data. All samples showed strong genetic affinity to many CAS samples across a wide range of Indian Ocean coastal and island regions, with divergence time estimated around 4000 years ago. These findings support that the Madagascar house mice started to colonize the island with human agricultural activity, and experienced complex history for the establishment.

genetics↗